Functional and Gait Assessment in Children and Adolescents Affected by Friedreich’s Ataxia: A One-Year Longitudinal Study

<div><p>Friedreich’s ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich’s ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich’s ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich’s ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs.</p></div

Patients clinical and demographic overview.

<p>Patients clinical and demographic overview.</p

Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signaling

Distal Hereditary Motor Neuropathies (dHMNs) are clinically and genetically heterogeneous neurological conditions characterized by degeneration of the lower motor neurons. So far, 18 dHMN genes have been identified, however about 80% of dHMN cases remain without a molecular diagnosis.By a combination of autozygosity mapping, identity-by-descent segment detection and whole-exome sequencing approaches we identified two novel homozygous mutations in the SIGMAR1 gene (p.E138Q and p.E150K) in two distinct Italian families affected by an autosomal recessive form of HMN.Functional analyses in several neuronal cell lines strongly support the pathogenicity of the mutations and provide insights into the underlying pathomechanisms involving the regulation of ER-mitochondria tethering, Ca(2+) homeostasis and autophagy. Indeed, in\ua0vitro, both mutations reduce cell viability, the formation of abnormal protein aggregates preventing the correct targeting of sigma-1R protein to the mitochondria-associated ER membrane (MAM) and thus impinging on the global Ca(2+) signaling.Our data definitively demonstrate the involvement of SIGMAR1 in motor neuron maintenance and survival by correlating, for the first time in the Caucasian population, mutations in this gene to distal motor dysfunction and highlight the chaperone activity of sigma-1R at the MAM as a critical aspect in dHMN pathology

Ankle, hip and knee rotational co-variation during a complete gait cycle.

<p>The figure depicts the angles of hip, knee and ankle during the gait cycle on 3D plot, that is, the angle values on vertical axes of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162463#pone.0162463.g001" target="_blank">Fig 1</a> for hip, knee and ankle was bring back, respectively on x, y and z axes, in this figure. This figure represents the lower limb joint co-variation during the gait cycle. Solid line represents the mean values of controls, dotted line the baseline of FRDA, and dashed line the FRDA follow-up. Dark gray arrows indicate the foot landing, that is, the gait cycle start. White arrows indicate the beginning of the swing phase. The large light gray arrow represents the gait pattern progressive deterioration towards ankle and knee extension moving from the dotted to the dashed curves in patients with FRDA (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162463#pone.0162463.s001" target="_blank">S1 Fig</a> for a 3D animation of the graph).</p

Kinetic/Kinematics parameters.

<p>The figure shows the time series of the variables examined in the paper. In the horizontal axis is represented the time normalized respect to the duration of the gait cycle (from the hell contact to the floor to the ipsilateral succeeding hell contact). The arrows indicate the peak values here studied. The black line represents the mean values of the baseline of the patient with FRDA, while the gray band represents the standard deviation of the control group. In the first row are represented in degree the flexion and extension rotation of the hip, the knee and the ankle, from left to right respectively. In the second and third rows are represented joints moment and power, respectively, normalized respect to body wheight. In the four row is represented the hip ab-adduction and the angle of the internal end external rotation of the foot.</p

T-test results on average values and standard deviations of kinetic/kinematic parameters of Gait Analysis: FRDA (1^st assessment) vs Controls.

<p>T-test results on average values and standard deviations of kinetic/kinematic parameters of Gait Analysis: FRDA (1^st assessment) vs Controls.</p